The substantia nigra (SN) is a critical site at which GABA agonist drugs act to exert anticonvulsant actions in a variety of experimental seizure models in the rodent. The anticonvulsant actions evoked from SN have been shown to be mediated via disinhibition of the deep superior colliculus (DSC). The goal of the research in the present proposal is to extend our knowledge of the functional neuroanatomy of the nigral circuitry with respect to seizure control in several important respects: 1) To determine the role of serotonin (5HT) in SN for regulation of seizure susceptibility and to examine interactions between manipulations of 5HT and GABA-mediated transmission in SN in seizure control. These studies, which are an outgrowth of our recent findings that intranigral 5HT agonists exert anticonvulsant actions, will test the hypothesis that 5HT activity can compensate for a loss of GABA function in SN with respect to maintaining seizure control; 2) To determine whether intranigral GABA agonist treatment can attenuate neuronal damage induced by prolonged seizure activity in the rat. These studies (prompted by our recent evidence that unilateral GABA agonist treatment in SN attenuates the seizure-evoked increase in regional glucose utilization without attenuating the seizures) will test the hypothesis that GABA-mediated inhibition of the SN in one hemisphere will protect against seizure-induced neuronal damage in the same hemisphere even though the seizures themselves are not suppressed; 3) To determine whether the anticonvulsant action of GABA-mediated inhibition in SN can be extended to the primate brain. By using an acute focally- evoked seizure model which we have developed in the nonhuman primate, we will test the hypothesis that enhancing GABA-mediated transmission bilaterally in the SN of the monkey will be anticonvulsant; 4) To determine whether the anticonvulsant action of GABA receptor blockade in the DSC can be extended to the primate brain, using the same seizure model as in (3) above; 5) To evaluate the influence of the DSC on the initiation and propagation of seizure discharge in the limbic system of the rat. These studies will use depth EEG recording to test the hypothesis that blockade of GABA in the DSC interrupts the development of seizure discharge throughout the limbic circuitry; 6) To determine whether excitatory inputs to SN from the subthalamic nucleus (STN) play an important role in regulating seizure susceptibility. These studies will test the hypothesis that inhibition of the STN bilaterally will exert an anticonvulsant effect by reducing excitatory inputs (mediated via excitatory amino acids) to SN: The results of the proposed studies will advance our understanding of the neurotransmitter receptor interactions in SN and interconnections with other regions such as DSC and STN which are important for seizure control. At the same time, the proposed experiments will verify the extent to which the basic findings with rodent models are applicable to the primate brain, thereby allowing for clinically relevant conclusions to be formulated. It is expected that novel therapeutic strategies for the control of seizure disorders may emerge from these investigations, and in addition, insights into sources of pathology that may contribute to the etiology of certain forms of human epilepsy may be generated.